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Drug Repositioning Bringing New Life to Shelved Assets and Existing Drugs von Barratt, Michael J. (eBook)

  • Erscheinungsdatum: 11.04.2012
  • Verlag: Wiley
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Drug Repositioning

The how's and why's of successful drug repositioning
Drug repositioning, also known as drug reprofiling or repurposing, has become an increasingly important part of the drug development process. This book examines the business, technical, scientific, and operational challenges and opportunities that drug repositioning offers. Readers will learn how to perform the latest experimental and computational methods that support drug repositioning, and detailed case studies throughout the book demonstrate how these methods fit within the context of a comprehensive drug repositioning strategy. Drug Repositioning is divided into three parts: Part 1, Drug Repositioning: Business Case, Strategies, and Operational Considerations, examines the medical and commercial drivers underpinning the quest to reposition existing drugs, guiding readers through the key strategic, technical, operational, and regulatory decisions needed for successful drug repositioning programs. Part 2, Application of Technology Platforms to Uncover New Indications and Repurpose Existing Drugs, sets forth computational-based strategies, tools, and databases that have been designed for repositioning studies, screening approaches, including combinations of existing drugs, and a look at the development of chemically modified analogs of approved agents. Part 3, Academic and Non-Profit Initiatives & the Role of Alliances in the Drug Repositioning Industry , explores current investigations for repositioning drugs to treat rare and neglected diseases, which are frequently overlooked by for-profit pharmaceutical companies due to their lack of commercial return. The book's appendix provides valuable resources for drug repositioning researchers, including information on drug repositioning and reformulation companies, databases, government resources and organizations, regulatory agencies, and drug repositioning initiatives from academia and non-profits. With this book as their guide, students and pharmaceutical researchers can learn how to use drug repositioning techniques to extend the lifespan and applications of existing drugs as well as maximize the return on investment in drug research and development.


    Format: ePUB
    Kopierschutz: AdobeDRM
    Seitenzahl: 416
    Erscheinungsdatum: 11.04.2012
    Sprache: Englisch
    ISBN: 9781118274392
    Verlag: Wiley
    Größe: 6970 kBytes
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Drug Repositioning



Drug repositioning, also commonly referred to as drug reprofiling or repurposing, has become an increasingly important part of the drug development process for many companies in recent years. The process of identifying new indications for existing drugs, discontinued, or "shelved" assets and candidates currently under development for other conditions - activities we refer to as "indications discovery" - is an attractive way to maximize return on prior and current preclinical and clinical investment in assets that were originally designed with different patient populations in mind. It is widely appreciated that the business impetus to recoup the vast investments in pharmaceutical research and development (R&D) is enormous. As discussed by Arrowsmith and Harrison in Chapter 1, output of new medical entities (NMEs) approved by the U.S. Food and Drug Administration (FDA) has remained steady at around 25 per year over the last decade, while pharmaceutical R&D expenditure has increased over 50% in the same time frame [1, 2]. Against this backdrop of escalating costs associated with increased development timelines and requirements, along with growing regulatory and reimbursement pressures, drug repositioning has emerged as a lower cost and potentially faster approach than de novo drug discovery and development. The objective of Part I of this book is to examine in detail the medical and commercial drivers underpinning the repositioning industry, and to highlight the key strategic, technical, operational, and regulatory considerations for drug repositioning programs.

Among the numerous case studies that are described throughout this book, perhaps the best known example of successful implementation of drug repositioning is that of the blockbuster and first approved treatment for erectile dysfunction (ED), Viagra® (sildenafil citrate). The story of the development of this drug, which was originally being developed by Pfizer for the treatment of angina, offers a fascinating insight into how keen observation and good science can unlock the full potential of safe biotherapeutics that are either already marketed or, as was the case for sildenafil, under development for other indications [3]. This example serves to highlight some of the essential elements that underpin the rationale behind, and opportunities that exist in, drug repositioning.

At its core, drug repositioning takes advantage of three fundamental principles. First is the reality of biological redundancy, namely that "druggable" biological targets can contribute to the etiologies of seemingly unrelated conditions, due to common underlying pathology and/or shared biological signaling networks. In the mid-1980s, the biological target of Viagra®, an enzyme called phosphodiesterase 5 (PDE5), was being studied for its involvement in regulating nitric oxide (NO) signaling in smooth muscle cells associated with coronary blood vessels. NO activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), leading to smooth muscle relaxation, increased blood flow, and the associated hemodynamic effects characteristic of nitrates. cGMP PDE enzymes such as PDE5 inactivate cGMP by converting it into guanosine monophosphate (GMP), and attenuate NO signaling. With this underlying biology in mind, sildenafil was at the time being considered as an antiangina therapy. After initial clinical trials in angina indicated modest hemodynamic effects (i.e., efficacy) but dose-limiting adverse events including erections, attention turned to ED, where the role of NO/cGMP was emerging at the time; but the role of PDE5 in the corpus cavernosum of the penis had not previously been appreciated [3]. New biology was thus uncovered and the rest, as they say, is history.

A second key driver for drug

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